The Serotonin Reuptake Inhibitor Sertraline Reduces Excessive Alcohol Consumption in Nonhuman Primates: Effect of Stress J
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The Serotonin Reuptake Inhibitor Sertraline Reduces Excessive Alcohol Consumption in Nonhuman Primates: Effect of Stress J. Higley, Ph.D., M. Hasert, M.S., S. Suomi, Ph.D., and M. Linnoila, M.D., Ph.D. Many monkeys that are reared without adult influence, when the stress was repeated, alcohol consumption fell with only peers, voluntarily consume alcohol in amounts below baseline and placebo levels. Sertraline treatment was producing intoxication on a relatively regular basis. Using ineffective in reducing consumption during the stressful a cross-over design, eight adolescent, peer-reared rhesus period of home-cage reunion, a period characterized by high monkeys were allowed unfettered access to an 8.4% ethanol levels of aggressive behavior. Behaviorally, sertraline solution and treated with 20 mg/kg/24 h of sertraline reduced aggression and anxiety-like self-directed behaviors. during three phases: home-cage, social separation, and Our findings provide evidence that sertraline may be an reunion with cage-mates. Although there was no immediate effective pharmacological treatment for excessive alcohol effect, sertraline reduced alcohol consumption beginning the consumption and aggression. On the other hand, stress second week of home-cage treatment, but only in subjects during treatment may reduce sertraline’s effectiveness as a that consumed large amounts of alcohol. Initially, the social treatment for excessive alcohol consumption. separation stress caused the sertraline-treated subjects’ [Neuropsychopharmacology 18:431–443, 1998] alcohol consumption rates to return to baseline levels, but Published by Elsevier Science Inc. KEY WORDS: Alcoholism and alcohol abuse; Primate; at risk for or who exhibit early onset alcohol abuse and Sertraline; Serotonin; Aggression; Stress alcoholism (for recent reviews see LeMarquand et al. 1994a; Litten et al. 1996; Pettinati 1996). Some recent A large number of preclinical studies have reported studies show that selective serotonin reuptake inhibi- high rates of alcohol consumption among animals with tors (SSRIs) are promising as adjunctive pharmacologi- reduced central nervous system (CNS) serotonin func- cal treatment for maintenance of abstinence (see LeMar- tioning (for reviews, see Sellers et al. 1992; LeMarquand quand et al. 1994b). Preclinical studies with rodents et al. 1994b). Among humans, clinical studies show evi- show that the SSRIs reduce alcohol consumption dence of reduced CNS serotonin functioning in subjects (LeMarquand et al. 1994b). Similarly, in a number of small scale studies, SSRIs have shown promise as an ad- junct treatment for alcohol abuse and alcoholism From the Section on Neurochemistry and Neuro-endocrinology, (LeMarquand et al. 1994a; Pettinati 1996). The con- Primate Unit, Laboratory of Clinical Studies, Primate Unit, DICBR, trolled studies conducted by Gorelick (1989) and Kranz- NIAAA (JH, MH, ML), and Laboratory of Comparative Ethology, NICHD (SS), Poolesville, Maryland. ler et al. (1995) showed, however, that fluoxetine was Address correspondence to: Dr. J.D. Higley, Laboratory of Clini- ineffective in promoting maintenance of abstinence cal Studies, DICBR, NIAAA, Section on Neurochemistry and Neu- among treatment-seeking alcoholics. More recently, re- roendocrinology, Primate Unit, Poolesville, MD 20837. Received April 23, 1997; revised September 1, 1997; accepted Sep- searchers used a controlled study to demonstrate that tember 3, 1997. citalopram was efficacious in promoting maintenance NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 6 Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(97)00180-2 432 J. Higley et al. NEUROPSYCHOPHARMACOLOGY 1998–VOL. 18, NO. 6 of abstinence among early-onset, violent male alcohol- jects reared by their mothers (Higley et al. 1994; 1996d). ics thought to have reduced central serotonin function- Because they share biochemical and behavioral similar- ing (Tiihonen et al. 1996). Because of the conflicting re- ities with some types of human alcoholics, and because ports on the efficacy of the SSRIs in the maintenance of they are more likely than normally reared monkeys to abstinence, we decided to investigate sertraline as a po- consume alcohol at rates that produce intoxication, tential treatment for excessive alcohol intake, using a peer-reared monkeys appear to be well suited to evalu- nonhuman primate model with monkeys known to ate pharmacological treatments for excessive consump- have reduced central serotonin functioning (Higley et tion. Based on what is known about peer-only reared al. 1996d,e). Furthermore, we designed the study specif- subjects, we hypothesized that sertraline would reduce ically to examine the role that stress plays in excessive their day-to-day alcohol consumption, particularly dur- alcohol consumption among nonhuman primates and ing nonstressful home-cage interactions. to test the efficacy of sertraline in mitigating the effects Previous studies have suggested that the effect of the of stress on alcohol consumption. SSRIs on alcohol consumption is not uniform across all Until recently, it was widely believed that nonhu- subjects. For example, Balldin and colleagues (Balldin et man primates would not voluntarily consume alcohol al. 1994) found that human subjects with modestly ele- in appreciable quantities (e.g., Mello and Mendelson vated rates of alcohol consumption (below 107 g per 1971; Meisch et al. 1975; Crowley et al. 1983); conse- day, mean consumption 85 g per day) were particularly quently, they were not typically used in research on al- likely to reduce their alcohol consumption after SSRI cohol abuse. More recent studies have shown, however, treatment as compared with subjects with very high that for many species of primates, many (but not all) consumption rates (above 107 g, mean consumption 138 subjects will freely consume alcohol in quantities that g per day). On the other hand, studies show that pri- produce pharmacological effects when an alcohol solu- mates with the lowest CNS serotonin functioning tend tion is palatable (Higley et al. 1991; Higley 1996; Higley to be the highest alcohol consumers (Higley et al. 1991, and Linnoila 1997). Within some species, such as rhesus 1996e), and alcoholics and sons of alcoholics also show macaques and other Old World primate species, some low CNS serotonin functioning (Ballenger et al. 1979; individual subjects will routinely consume sufficient Banki 1981; Borg et al. 1985). It is therefore not unrea- quantities of alcohol to produce blood levels exceeding sonable to predict that the subjects with the highest con- the limits of legal intoxication for most states in the sumption patterns would benefit most from SSRI treat- United States, and at times drink amounts that produce ment. Thus, we further hypothesized that sertraline stupor and unconsciousness (Erwin et al. 1979; Ervin et treatment would be most effective in those subjects al. 1990; Higley et al. 1991). Most rhesus monkeys are whose consumption rates were high and whose con- modest consumers, however, with only 15–20% consum- sumption patterns were less restrained. ing alcohol in daily quantities that produce intoxication. Studies have also shown that anxiety-like behaviors More recent studies of alcohol consumption in non- and high levels of stress are positively correlated with human primates have investigated variables that are as- the level of alcohol consumption (Kraemer and McKin- sociated with high alcohol consumption. Results from ney 1985; Higley et al. 1991, 1996e). Social separation these studies parallel investigations in humans showing stress (removal and isolation of subjects from their so- that low CSF 5-hydroxyindoleacetic acid (5-HIAA) and cial group) increases alcohol consumption, even among 3-methoxy-4-hydroxyphenylgycol (MHPG) are corre- subjects not particularly prone to overconsume alcohol lated with excessive alcohol consumption (Higley et al. (Kraemer and McKinney 1985; Higley et al. 1991). Among 1991; 1996e). Another factor that increases alcohol con- humans who receive antidepressants for the treatment sumption in nonhuman primates such as rhesus of unipolar depression, some studies show that stress macaques involves an early rearing history in which increases probability of relapse (Belsher and Costello young subjects are raised in social groups that do not 1989; Leverich et al. 1990). Some studies also show that contain adults (peer-only reared subjects—Higley et al. stressful conditions increase the probability of relapse 1991, 1996e). Subjects reared early in life with only among abstinent alcoholics (Brown et al. 1990), and in- same-aged peers, for example, are about twice as likely dividuals who relapse after treatment are more likely to to consume alcohol at rates that produce daily intoxica- report high levels of state and trait anxiety (Brown et al. tion as subjects reared early in life by their parents (Hig- 1991). Such findings suggest that stress may attenuate ley et al. 1991, 1996e). Peer-only reared subjects also the effect of a pharmacological treatment and led us to show low concentrations of CSF 5-HIAA and MHPG test the effectiveness of sertraline in peer-reared mon- (Higley et al. 1991, 1996d,e). Like human subjects with keys under both baseline and stressful conditions. Spe- low CSF 5-HIAA concentrations when peer-only reared cifically, we hypothesized that sertraline would reduce subjects mature to adulthood, they are excessively ag- alcohol consumption during baseline